PROJECT SUMMARY: CANCER EPIGENETICS RESEARCH PROGRAM The Sylvester Comprehensive Cancer Center (Sylvester) Cancer Epigenetics (CE) Research Program, established in 2014, comprises 18 investigators from seven departments. Co-led by Ramin Shiekhattar, PhD, and Maria Figueroa, MD, the program aims to incorporate basic and clinical research in the field of cancer epigenetics to pinpoint epigenetic factors that contribute to cancer risk, initiation, progression, and treatment response, taking into consideration the specific needs present within Sylvester?s catchment area. To achieve these objectives, the CE program encompasses three specific aims: 1) Elucidate the oncogenic molecular mechanisms associated with epigenetic regulators that are mutated in cancer; 2) Define the enhancer and transcriptional reprogramming that is imposed through aberrant signal transduction cascades in cancer; and 3) Validate epigenetic targets for therapeutic intervention and biomarker development in pre-clinical and clinical studies. Currently, program members receive $5.5M in annual direct peer-reviewed funding, including $2.2M from the NCI and $1.5M from other NIH Institutes. CE?s research efforts rely heavily on Sylvester?s shared resources, notably the Onco-Genomics, Flow Cytometry, and Biostatistics and Bioinformatics Shared Resources. The CE program fosters robust intra- and inter-programmatic collaborations as well as inter- institutional collaborations to leverage the depth and breadth of member expertise in basic, translational, and clinical research and develop innovative approaches to ameliorate the impact of cancer in Sylvester?s catchment area, a four-county area known as South Florida. For instance, CE works collaboratively with the Tumor Biology Research Program to understand the interplay between oncogenic signaling pathways and epigenetic deregulation in cancer, and with the Cancer Control Research Program to understand how specific environmental and socio-economic disparities impact the epigenome and influence cancer initiation and progression. These collaborative efforts are supported by a rapidly expanding portfolio of peer-reviewed funding, including an NCI Pioneer Award, multi-PI R01 grants, a recently awarded Leukemia and Lymphoma Society (LLS) Scholar Award, and an LLS Specialized Center of Research program project grant. Several investigator-initiated studies are also emerging from CE program discoveries. Furthermore, CE members have published 143 cancer-relevant papers since 2014; 24% represent intra-programmatic, 29% represent inter- programmatic, and 77% reflect multi-institutional collaborations. Some of CE?s major contributions include 1) dissecting the role of DNA methylation and hydroxymethylation in the hematological malignancies; 2) targeting histone readers, writers, and erasers in AML; and 3) defining the role of BAP1 and ASXL1 in uveal melanoma and their contribution to histone methylation and ubiquitination; and 4) discovering of enhancer RNAs (eRNAs) and targeting eRNAs in cancer to affect pathogenic gene expression and cellular growth.